PROJECT SUMMARY Protein-ligand interactions are fundamental to virtually all biological organisms and thus are the primary focus of pharmaceutical therapies. Yet these interactions are difficult to study due to current limitations in available structural methods. 3D atomic structures of protein-ligand complexes have dramatically increased our understanding of molecular recognition, resulting in the development of structure-based drug design and its fundamental integration into medicinal chemistry. X-ray crystallography is the primary tool for structure determination of macromolecules and is capable of elucidating high-resolution atomic interactions between proteins and ligands, yet suffers from experimental limitations such as the bottleneck of crystallization and the inability to reveal dynamic structural states. Solution scattering provides a mechanism for modeling the structure and dynamics of molecules in solution, yet current methods only provide low-resolution information, insufficient for characterizing atomic level interactions between ligands and proteins. Here we propose a collection of new algorithms combining solution scattering with structural information obtained by methods such as crystallography for the determination of high-resolution structure and dynamics of protein-ligand complexes in solution. The successful completion of the aims of this proposal will enable researchers to identify the atomic-level interactions resulting in molecular recognition of ligands such as drugs and other small molecules. As solution scattering experiments can be performed in high-throughput, these developments promise to increase the rate at which pharmaceuticals can be screened and characterized. These insights will ultimately play an important role in developing novel therapeutics and improving approaches to structure-based drug design, allowing for more specific and effective treatments of a wide range of diseases.